Methods and systems for supplying aerosolization devices with liquid medicaments

ABSTRACT

A method is described for supplying a metered amount of a liquid medicament to an aerosolizing device. The method utilizes a dispenser comprising an elongate dispenser body having a proximal end and a tip at a distal end through which a liquid medicament is dispensed. The dispenser further comprises a dispensing mechanism that operates to dispense a metered quantity of the liquid medicament from the tip each time the dispenser body is compressed. The dispenser is grasped with one hand such that the fingers wrap around the dispenser body, with the thumb closest to the proximal end and the last finger closest to the tip. The tip is inserted into an opening of an inhaler and the elongate body is forced toward the tip to cause the dispenser body to compress, thereby operating the dispensing mechanism and causing a metered quantity of the liquid medicament to eject into the inhaler.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a nonprovisional application claiming the benefit ofU.S. Provisional Application No. 61/624,531, filed Apr. 16, 2012, thecomplete disclosure of which is herein incorporated by reference.

BACKGROUND OF THE INVENTION

Various types of inhalers exist for aerosolizing liquids. For example,U.S. Pat. No. 5,586,550, incorporated herein by reference, describes aninhaler that comprises a dispensing apparatus in which a membrane withtapered apertures is vibrated such that liquid in contact with a rearface of the membrane is dispensed from a front face of the membrane asan aerosol. Other examples of single dose inhaler systems andmedicaments that may be aerosolized are described in U.S. PatentPublication Nos. 2011/0168172 and 2001/0168170, the disclosures of whichare herein incorporated by reference.

One aspect of such inhalers is the need to supply a metered amount ofliquid medicament to the dispensing apparatus so that the metered amountmay be aerosolized and delivered to the patient's lungs. However,delivering a known quantity of a liquid medicament (that typically mustbe stored in a sterile environment) has proven to be challenging,particularly when the metered quantity needs to be dispensed in acontrolled and repeatable fashion. Hence, this invention relates to waysfor delivering such medicaments to inhalers for subsequent aerosolizing.

BRIEF SUMMARY OF THE INVENTION

One embodiment provides a method for supplying a metered amount of aliquid medicament to an aerosolizing device in a repeatable manner. Themethod utilizes an aerosolization device comprising a housing having amouthpiece, a vibratable member within the housing and disposed to ejectliquid droplets through the mouthpiece, a reservoir to hold the liquidmedicament until aerosolized by the vibratable member, and an opening inthe housing and in communication with the chamber. While described inconnection with one specific type of inhaler, it will be appreciatedthat other types of aerosolization devices could be used with themethods described herein.

To supply a metered amount of liquid medicament, a dispenser is usedthat comprises an elongate dispenser body having a proximal end and atip at a distal end through which a liquid medicament is dispensed. Thedispenser further comprises a dispensing mechanism that operates todispense a metered quantity of the liquid medicament from the tip eachtime the dispenser body is compressed.

One critical factor of the method is the manner in which the dispenseris held and operated by a user. To facilitate dispensing, the dispensermay be grasped with one hand such that the fingers wrap around thedispenser body, with the thumb closest to the proximal end and the lastor pinky finger closest to the tip. The tip of the dispenser is insertedinto the opening in the housing. Then, while grasping the dispenser inthe manner described, the elongate body is forced toward the tip tocause the dispenser body to compress, thereby operating the dispensingmechanism and causing a metered quantity of the liquid medicament toeject into the chamber each time the dispenser body is compressed.

Because the prescription may call for more medicament than can besupplied with a single ejection from the dispenser, the process may berepeated for as many times as is needed to supply the prescribed amountinto the chamber. This may be done with a “pumping action” where theuser “pumps” the dispenser (causing it to compress with each pump),until the correct number of pumps have been supplied. For example, ifthe prescription calls for a certain volume of the liquid medicament,the dispenser may be pumped five times, with each pump dispensing adroplet having a metered volume of one-fifth the total volume.

In some cases, the tip may include at least one alignment feature thatassists to keep the dispenser generally perpendicular to the housingwhile dispensing the liquid medicament. Once the metered amount has beendispensed into the chamber, the vibratable member is actuated to ejectthe dispensed liquid medicament as an atomized spray.

In another embodiment, the invention provides an exemplaryaerosolization system. The system includes an aerosolization devicecomprising a housing having a mouthpiece, a vibratable member within thehousing and disposed to eject liquid droplets through the mouthpiece, areservoir to hold the liquid medicament until aerosolized by thevibratable member, and an opening in the housing that is in fluidcommunication with the chamber.

The system further includes a dispenser comprising an elongate dispenserbody having a proximal end and a tip at a distal end through which aliquid medicament is dispensed. The dispenser further comprises adispensing mechanism that operates to dispense a metered quantity of theliquid medicament from the tip each time the dispenser body iscompressed. The dispenser is separate from the housing so that it may bemanually interfaced with the aerosolization device.

Further, the opening defines an interface that engages with the tip suchthat when the tip is inserted into the opening, the interface stabilizesthe dispenser in an upright orientation outside of the housing to permitthe dispenser to be grasped with one hand to dispense the medicament.For example, this orientation permits a user to wrap the fingers aroundthe dispenser body, with the thumb closest to the proximal end and thelast finger closest to the tip, and while grasping the dispenser,forcing the elongate body toward the tip to cause the dispenser body tocompress, thereby operating the dispensing mechanism and causing ametered quantity of the liquid medicament to eject into the chamber eachtime the dispenser body is compressed.

In one important aspect, the tip may include at least one alignmentfeature that assists to keep the dispenser generally perpendicular tothe top surface of the housing while dispensing the liquid medicament.This alignment feature may comprise a circular step around the tip, aplurality of tabs protruding from the tip, and the like.

In yet another embodiment, the invention provides an exemplary methodfor supplying a metered amount of a liquid medicament to an aerosolizingdevice. The method utilizes an aerosolization device comprising ahousing having a mouthpiece, a vibratable member within the housing anddisposed to eject liquid droplets through the mouthpiece, and areservoir to hold the liquid medicament until aerosolized by thevibratable member. The housing also includes a top surface and anopening in the top surface of the housing. The opening is in fluidcommunication with the chamber.

The method also utilizes a dispenser that comprises an elongatedispenser body having a proximal end and a tip at a distal end throughwhich a liquid medicament is dispensed. The dispenser further comprisesa dispensing mechanism that operates to dispense a metered quantity ofthe liquid medicament from the tip each time the dispenser body iscompressed.

With this configuration, the tip is inserted into the opening in thehousing such that the dispenser body is generally perpendicular to thetop surface of the housing and is seated within the opening such thatthe dispenser body is self-standing outside of the housing. In thisorientation, the dispenser body may be compressed to operate thedispensing mechanism and cause a metered quantity of the liquidmedicament to eject into the chamber each time the dispenser body iscompressed.

The dispenser may be repeatedly compressed to dispense multiple meteredquantities of the liquid medicament into the chamber. Further, the tipmay include one or more alignment features that assist to keep thedispenser generally perpendicular to the housing while dispensing theliquid medicament so that it may be aerosolized.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates one method for grasping a dispenser in preparationfor delivering a metered amount of liquid medicament to an aerosolizingapparatus.

FIG. 2 illustrates the dispenser of FIG. 1 when inserted into theaerosolizing apparatus and compressed in order to deliver the liquidmedicament.

FIG. 3 illustrates the dispenser of FIG. 1 when initially inserted intothe aerosolizing apparatus of FIG. 1.

FIG. 4 illustrates the dispenser of FIG. 3 when compressed or pumped todeliver the liquid medicament.

FIG. 5 is a cross sectional side view of another embodiment of anaerosolizing apparatus according to the invention.

FIG. 6 illustrates another embodiment of a dispenser having ribs tofacilitate positioning of the dispenser.

DETAILED DESCRIPTION OF THE INVENTION

Certain aspects of the invention relate to techniques for dispensingmetered quantities of a liquid medicament into an aerosolizingapparatus, also referred to as an inhaler. Although useful with a widevariety of aerosolizing devices, in some cases the liquid will bedispensed into an aerosolizing apparatus comprising a housing defining adispensing outlet or mouthpiece, a vibratable membrane or mesh having afront face exposed at the outlet and a rear face for receiving a liquidto be dispensed, and a vibrating mechanism connected to the housing andoperable to vibrate the membrane to dispense aerosol of the liquidthrough the membrane.

A variety of containers or dispensers may be used to store the liquidmedicament, then to deliver a metered quantity of the liquid into areservoir where it will contact the rear face of the membrane. In thisway, a metered quantity of liquid is dispensable at the outlet ormouthpiece by operating the vibrating mechanism for an operating periodsufficient to completely aerosolize the metered quantity at the rearface. The containers or dispensers will typically have a sealed regionwhere the liquid is stored and a mechanism for dispensing a meteredamount of liquid each time the mechanism is operated. For example, thecontainer may be compressed or pumped to eject a droplet of a knownvolume.

Exemplary aerosol generators that may be used in such inhalers are alsodescribed in U.S. Pat. Nos. 5,164,740; 6,629,646; 6,926,208; 7,108,197;5,938,117; 6,540,153; 6,540,154; 7,040,549; 6,921,020; 7,083,112;7,628,339; 5,586,550; 5,758,637; 6,085,740; 6,467,476; 6,640,804;7,174,888; 6,014,970; 6,205,999; 6,755,189; 6,427,682; 6,814,071;7,066,398; 6,978,941; 7,100,600; 7,032,590; 7,195,011, and in U.S.Patent Publication Nos. 2011/0168172 and 2001/0168170, all incorporatedherein by reference. These references describe exemplary aerosolgenerators and ways to manufacture such aerosol generators. Each areincorporated by reference for at least these features. The aerosolgenerators may comprise vibratable membranes having tapered aperturewith a size in the range from about 3 μm to about 8 μm, preferably fromabout 3 μm to about 6 μm, and in some cases around 4 μm. The membranemay be domed shaped and be vibrated by an annular piezoelectric elementthat circumscribes the apertures. The diameter of the membrane may be inthe range from about 5 mm to about 8 mm. The membrane may also have athickness in the range from about 50 microns to about 70 microns.Typically, the membrane will be vibrated at a frequency in the rangefrom about 50 kHz to about 150 kHz.

A variety of liquid medicaments may be dispensed from the container. Forexample, the liquid medicament may comprise an insulin formulation, suchas a preservative free insulation, including any of those described inU.S. Patent Publication No. 2011/0168170, previously incorporated byreference. For example, a preservative free insulin formulation that maybe dispensed may be free of any preservatives, including phenol,metacresol, chloro-cresol, thymol and mixtures thereof or the like. Theabsence of such preservatives enable the formulations to be aerosolizedas a liquid spray using a vibrating mesh or aperture plate that operatesat high frequencies. The absence of such preservatives permits a dosageof the formulation to come into contact with the vibrating mesh withoutsubstantial foaming of the formulation. In turn, the formulation may beaerosolized more quickly. Further, substantially all of the liquid isable to be aerosolized. Such formulations contain water in major andhuman insulin in minor amount. The formulations may also include variousconcentrations of human insulin. For example, the concentrations may bein the range from about 100 IU insulin/ml of formulation to about 1200IU insulin/ml of formulation, and more preferably from about 200 IUinsulin/ml of formulation to about 800 IU insulin/ml of formulation. Inaddition to water and human insulin, the formulations may also includezinc, acetate, chloride and sodium. The zinc ion and acetate ion comefrom the drug substance, e.g., the insulin. The chloride ion and sodiumion are added during dissolution of the insulin and adjustment of thepH. Merely by way of example, the NaCl concentration may be about 20 mMfor an 800 IU insulin/ml formulation, about 10 mM for a 400 IUinsulin/ml formulation, and about 5 mM for a 200 IU insulin/mlformulation.

Other liquid medicaments may also be dispensed. For example, suchmedicaments could include other protein formulations, asthma and COPDtreatments, vaccines and pain relief treatments.

Referring now to the Figures, one exemplary method for dispensing ametered amount of medicament into an inhaler will be described. Shown inFIG. 1 is an inhaler 10 that is constructed of a housing 12 having amouthpiece 14. Disposed within the housing is an aerosol generatorcomprising a vibratable mesh similar to those described herein, as wellas electronics to control operation of the aerosol generator. The meshis positioned to eject an aerosol through mouthpiece 16 when the mesh isvibrated. Housing 12 includes a top surface 13 with a slidable cover 18is positioned over an opening 20 (see FIG. 2). Cover 18 is slid back isto expose opening 20. Further, opening 20 leads to a reservoir 22 orfunnel (see FIGS. 3 and 4) that tapers toward a vibratable mesh 24 thatis part of an aerosol generator that may be similar to any of thosedescribed herein. More specifically, mesh 24 has a rear face that isexposed to reservoir 22 so that when liquid is supplied to reservoir 22it comes into contact with the rear face of mesh 24. When mesh 24 isvibrated (by actuating an “on” button 26 that energizes the aerosolgenerator) the liquid is ejected from the front face of mesh 24 as anatomized spray and is available for inhalation through mouthpiece 14.

FIG. 5 illustrates the internal components of an inhaler 100 that issimilar to inhaler 10 as previously described. Inhaler 100 isconstructed of a housing 112 that includes an opening 120 leads to areservoir 122 that has an open bottom end 150 that funnels the dispensedliquid onto the rear face of a vibratable mesh (not shown) that is partof an aerosol generator 154 that has a vibratable element 155 (such asan annular piezoelectric transducer) that vibrates the mesh. Aerosolgenerator 154 has a circular opening 156 across which the mesh isdisposed. When vibrated, the mesh ejects the liquid as an aerosolizedspray into a capture chamber and to a mouthpiece. In this way, theaerosolized spray may be inhaled by inhaling from the mouthpiece.

In one embodiment, the liquid to be aerosolized is stored in a dispenser30 that is best illustrated in FIGS. 3 and 4. Dispenser 30 mayconveniently be described in terms of a proximal end 32 and a distal end34 that terminates in a tip 36. Dispenser 30 further includes a canister38 that stores the liquid medicament in a sterile environment. Dispenser30 includes an internal valve such that distal end 34 may be movedrelative to proximal end 32, thus compressing dispenser 30. In so doing,each time dispenser 30 is compressed (or “pumped”) a metered volume ofliquid is ejected into reservoir 22. For example, FIG. 3 shows dispenser30 in an uncompressed state. In FIG. 4, a force is applied to compressdispenser 30 and eject the droplet into the reservoir 22. A similarprocess may be used in connection with inhaler 100 where the liquid isinjected into reservoir 122. This process may be repeated as many timesas needed in order to dispense the proper volume of the liquidmedicament into reservoir 22. After dispersing the desired amount ofliquid medicament, dispenser 30 may be removed and stored for futureuse. Exemplary unit volumes that may be dispensed with each pump may bein the range from about 5 to about 100 microliters.

Tip 36 includes a shoulder 40 in the shape of an annular or circularstep that serves as a stop to prevent further insertion of tip 36 intoopening 20. Shoulder 40 is inset by a distance that is sufficient sothat it not only serves as a stop by also permits tip 36 to seat withinopening 20 in a stable position that is generally vertical to the topsurface 13 of housing 12. As such, once dispenser 30 is placed intoopening 20, it will be self-standing in a generally verticalorientation. This position permits a user to easily grasp the disperser30 when ready to dispense a unit volume of the liquid to the aerosolgenerator. Although shown with a shoulder, other seating mechanismscould be used, such as a taper that matches with the taper of opening20, protruding tabs or wings, detents, and the like.

One exemplary technique for operating dispenser 30 is illustrated inFIGS. 1 and 2. It will be appreciated that a similar process may be usedin connection with inhaler 100. In FIGS. 1 and 2, dispenser 30 isgrasped with one hand, such that the four fingers wrap around dispenser30, mostly about canister 38. By using four fingers to grasp dispenser30, a firm grip is achieved so that dispenser 30 may easily be pumped toeject the liquid. Further, the person's thumb may rest on proximal end32 to apply a further compressive force. With the proper grip, cover 18may be slid back and tip 34 placed into opening 20. As previouslydescribed, tip 34 includes a shoulder 40 that is wider than opening 20so as to prevent tip 34 from coming into contact with mesh 24. Further,shoulder 40 may be designed so that tip 34 is sufficiently spaced-apartfrom mesh 24 so that when the full metered amount of the liquid isdispensed into reservoir 22, tip 34 does not come into contact with thedispensed liquid. In this way, when dispenser 30 is removed from theinhaler, it will not also remove some of the dispensed liquid.Typically, tip 34 will be spaced apart from mesh 24 by a distance thatis in the range from about 5 mm to about 20 mm. Tip 34 may also betapered, such as to match the taper of reservoir 22. The taper ofreservoir 22 facilitates delivery of all the dispensed liquid onto therear face of mesh 24, and the tapering of tip 34 prevents it from cominginto contact with the walls of reservoir 22.

As best shown in FIG. 2, with tip 34 in place, the user presses canister38 toward tip 34. At the same time, inhaler 10 is held in place. Thiscauses dispenser 30 to compress. In turn, the internal valve is openedto permit a metered amount of liquid to be dispensed from tip 34 andinto reservoir 22. Each time canister 38 is pressed downward, or pumped,another metered amount of liquid is ejected. This maneuver is performedas many times as is needed in order to supplied the prescribed dosageinto reservoir 22.

By holding the dispenser 30 in the manner shown, this pumping action mayeasily occur. This is in contrast to a nasal spray dispenser, that istypically actuated in an upright manner by carefully and simultaneouslycompressing the proximal end with the middle and index finger (with thetip extending between the fingers) to the distal end of the dispensercontainer, that is held under equal pressure by the thumb. With thistype of nasal sprayer, the spray occurs when sufficient pressure isapplied equally to both ends. In contrast, dispenser 30 can be easilyactuated by applying pressure solely to the distal end of the dispenserwhen the tip is engaged with the inhaler device. The inhaler device andmating features are constructed so that a metered amount of medicamentis consistently delivered from the dispenser into the device and theuser may do so with unregulated pressure, provided the force is greaterthan or equal to that required to compress the dispenser throughout itsfull range. If the inhaler device is loaded while placed on a table orany other freely supported surface, the force required to compress thedispenser into the device to the point of actuation is reduced by 50%when compared to the amount of force required to disperse a volume ofliquid when holding both the device and dispenser (without the aid of asupport surface).

FIG. 6 illustrates an alternative embodiment of a dispenser 80 that maybe used with inhaler 10 or inhaler 100. Dispenser 80 has a tip 82 at itsdistal end with multiple alignment features 84 that assist to properlyalign and position tip 82 within opening 20 in top surface 13. Alignmentfeatures 84 may have a variety of shapes, sizes and configurations.Although shown with four equally spaced apart features 84, it will beappreciated that other numbers may be used, such as only a singlealignment feature. Features 84 serve as stops to limit insertion of tip82 into opening 20. Features 84 also provide a tactile feel to let theuser know when tip 82 has been properly inserted. When all four features84 engage the surface of inhaler 10, dispenser 80 has been properlyinserted and is ready to have a metered amount dispensed into inhaler10. Further, features 84 serve to hold dispenser 80 in a generallyvertical or perpendicular orientation relative to top surface 13. Inthis way, dispenser 80 is self-standing when inserted into opening 20 tomake it easier for a user to grasp and dispense as described inconnection with FIGS. 1 and 2.

The invention has now been described in detail for purposes of clarityand understanding. However, it will be appreciated that certain changesand modifications may be practiced within the scope of the appendedclaims.

What is claimed is:
 1. A method for supplying a metered amount of aliquid medicament to an aerosolizing device, the method comprising:providing an aerosolization device comprising a housing having amouthpiece, a vibratable member within the housing and disposed to ejectliquid droplets through the mouthpiece, a reservoir to hold the liquidmedicament until aerosolized by the vibratable member, and an opening inthe housing that is in fluid communication with the chamber; providing adispenser comprising an elongate dispenser body having a proximal endand a tip at a distal end through which a liquid medicament isdispensed, wherein the dispenser further comprises a dispensingmechanism that operates to dispense a metered quantity of the liquidmedicament from the tip each time the dispenser body is compressed;grasping the dispenser with one hand such that the fingers wrap aroundthe dispenser body, with the thumb closest to the proximal end and thelast finger closest to the tip; inserting the tip into the opening inthe housing; while grasping the dispenser, forcing the elongate bodytoward the tip to cause the dispenser body to compress, therebyoperating the dispensing mechanism and causing a metered quantity of theliquid medicament to eject into the chamber each time the dispenser bodyis compressed.
 2. A method as in claim 1, further comprising repeatedlyforcing the elongate body toward the tip to dispense multiple meteredquantities of the liquid medicament into the chamber.
 3. A method as inclaim 1, wherein the tip includes at least one alignment feature, andwherein the alignment feature assists to keep the dispenser generallyperpendicular to the housing while dispensing the liquid medicament. 4.A method as in claim 1, further comprising actuating the vibratablemember to eject the dispensed liquid medicament as an atomized spray. 5.An aerosolization system, comprising: an aerosolization devicecomprising a housing having a mouthpiece, a vibratable member within thehousing and disposed to eject liquid droplets through the mouthpiece, areservoir to hold the liquid medicament until aerosolized by thevibratable member, and an opening in the housing that is in fluidcommunication with the chamber; a dispenser comprising an elongatedispenser body having a proximal end and a tip at a distal end throughwhich a liquid medicament is dispensed, wherein the dispenser furthercomprises a dispensing mechanism that operates to dispense a meteredquantity of the liquid medicament from the tip each time the dispenserbody is compressed, wherein the dispenser is separate from the housing;wherein the opening defines an interface that engages with the tip suchthat when the tip is inserted into the opening, the interface stabilizesthe dispenser in an upright orientation outside of the housing to permitthe dispenser to be grasped with one hand such that the fingers wraparound the dispenser body, with the thumb closest to the proximal endand the last finger closest to the tip, and while grasping thedispenser, forcing the elongate body toward the tip to cause thedispenser body to compress, thereby operating the dispensing mechanismand causing a metered quantity of the liquid medicament to eject intothe chamber each time the dispenser body is compressed.
 6. A system asin claim 5, wherein the tip includes at least one alignment feature, andwherein the alignment feature assists to keep the dispenser generallyperpendicular to the top surface of the housing while dispensing theliquid medicament.
 7. A system as in claim 5, wherein the alignmentfeature comprises a circular step around the tip.
 8. A system as inclaim 7, wherein the alignment feature comprises a plurality of tabsprotruding from the tip.
 9. A method for supplying a metered amount of aliquid medicament to an aerosolizing device, the method comprising:providing an aerosolization device comprising a housing having amouthpiece, a vibratable member within the housing and disposed to ejectliquid droplets through the mouthpiece, and a reservoir to hold theliquid medicament until aerosolized by the vibratable member, whereinthe housing includes a top surface and an opening in the top surface ofthe housing, and wherein the opening is in fluid communication with thechamber; providing a dispenser comprising an elongate dispenser bodyhaving a proximal end and a tip at a distal end through which a liquidmedicament is dispensed, wherein the dispenser further comprises adispensing mechanism that operates to dispense a metered quantity of theliquid medicament from the tip each time the dispenser body iscompressed; inserting the tip into the opening in the housing such thatthe dispenser body is generally perpendicular to the top surface of thehousing and is seated within the opening such that the dispenser body isself-standing outside of the housing; compressing the dispenser body tooperate the dispensing mechanism and cause a metered quantity of theliquid medicament to eject into the chamber each time the dispenser bodyis compressed.
 10. A method as in claim 9, further comprising repeatedlyforcing the elongate body toward the tip to dispense multiple meteredquantities of the liquid medicament into the chamber.
 11. A method as inclaim 9, wherein the tip includes at least one alignment feature, andwherein the alignment feature assists to keep the dispenser generallyperpendicular to the housing while dispensing the liquid medicament. 12.A method as in claim 9, further comprising actuating the vibratablemember to eject the dispensed liquid medicament as an atomized spray.